Numerous studies suggest that both environmental and genetic factors are involved in the immunopathogenic mechanisms underlying sarcoidosis. It has been postulated that microbial stimulation in a susceptible host plays a significant role in this disease but no unifying pathogen has yet been identified. More importantly, the signaling pathways underlying chronic Th1-mediated pathology in sarcoidosis are unknown. Detection of uniquely conserved structures of bacteria occurs by specific host pattern-recognition receptors, such as the nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and Toll-like receptors (TLRs). Both receptors play a role in shaping innate and adaptive immunity. Upon microbial stimulation, TLRs and NLRs activate the transcription factor NF-kB and mitogen-activated protein kinase (MAPK) signaling cascades that regulate inflammatory genes and control both innate and adaptive immune responses. Among the three well defined MAPK pathways (JNK, ERK, and p38), p38 activation plays an essential role in induction of several inflammatory genes. Recently, we have shown that bronchoalveolar lavage (BAL) cells and alveolar macrophages (AMs) of sarcoid subjects exhibit constitutively active p38, but lack active ERK. Dual specificity phosphatase 1 (DUSP1), which is often referred to as MAP kinase phosphatase (MKP)-1, plays a central role in dephosphorylation and inhibition of active p38. Thus, lack of adequate negative regulation through MKP-1 may contribute to persistent inflammation in sarcoidosis. Our novel observation indicates that BAL cells and AMs from patients exhibit defective MKP-1 induction and sustained p38 phosphorylation with heightened inflammatory mediators in response to microbial stimulation. We hypothesize that the heightened inflammatory response in sarcoidosis is due, at least in part, to impaired negative feedback regulation of p38 as a result of MKP-1 (DUSP1) induction and a defective ERK activation in response to microbial stimulation. We further hypothesize that resolution of inflammation in response to corticosteroid therapy is dependent on induction and function of MKP-1. Additionally, we hypothesize that failure of MKP-1 induction is due to aberrant regulation of transcription factors required for MKP-1 transcription. We will test our hypothesis i three Specific Aims: 1- To test the hypothesis that defective ERK activation in response to microbial stimuli in sarcoidosis leads to failure of MKP-1 induction; 2- To determine the frequency of active p38 in patients with sarcoidosis in CD14+ AMs and to test the hypothesis that CD14+ peripheral blood mononuclear cells (PBMCs) parallel to p38 phenotype of AMs; and 3- To test the hypothesis that sarcoid AMs respond to microbial stimuli with aberrant expression or activity of transcription factors (TFs) involved in MKP-1 expression, and that effective drug treatment targets MKP-1 induction through modification of TFs.
Sarcoidosis is an inflammatory disorder of unknown origin affecting humans worldwide. We propose to study the regulation of inflammatory responses of bronchoalveolar lavage cells of these patients. The proposed studies will provide insight into the negative regulation of inflammation through MKP-1 in response to microbial constituents in sarcoidosis.
|Talreja, Jaya; Samavati, Lobelia (2018) K63-Linked Polyubiquitination on TRAF6 Regulates LPS-Mediated MAPK Activation, Cytokine Production, and Bacterial Clearance in Toll-Like Receptor 7/8 Primed Murine Macrophages. Front Immunol 9:279|
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|Bauerfeld, Christian; Samavati, Lobelia (2017) Role of MEK1 in TLR4 Mediated Signaling. J Cell Signal 2:|
|Talwar, Harvinder; Bauerfeld, Christian; Bouhamdan, Mohamad et al. (2017) MKP-1 negatively regulates LPS-mediated IL-1? production through p38 activation and HIF-1? expression. Cell Signal 34:1-10|
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|Talreja, Jaya; Talwar, Harvinder; Ahmad, Nisar et al. (2016) Dual Inhibition of Rip2 and IRAK1/4 Regulates IL-1? and IL-6 in Sarcoidosis Alveolar Macrophages and Peripheral Blood Mononuclear Cells. J Immunol 197:1368-78|
|Bouhamdan, Mohamad; Bauerfeld, Christian; Talreja, Jaya et al. (2015) MEK1 dependent and independent ERK activation regulates IL-10 and IL-12 production in bone marrow derived macrophages. Cell Signal 27:2068-76|
|Talwar, Harvinder; Rosati, Rita; Li, Jia et al. (2015) Development of a T7 Phage Display Library to Detect Sarcoidosis and Tuberculosis by a Panel of Novel Antigens. EBioMedicine 2:341-350|
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